Despite large-scale efforts devoted to the conduct of clinical trials in systemic lupus erythematosus (SLE), no new therapy has been approved for treatment of this disease in more than 50 years. Increased understanding of the immunologic mechanisms underlying SLE has led to the development of a variety of biologic agents that target specific aspects of the adaptive and innate arms of the immune system, including B cells, T cells, dendritic cells, and various cytokines. One of these agents, belimumab, was the subject of two positive phase 3 trials in nonrenal lupus that have given us hope that a new therapy for SLE may be finally within our grasp. In addition to these newer therapies, recent studies of standard-of-care medications such as mycophenolate mofetil and hydroxychloroquine have better defined the efficacy and safety of these agents for the treatment of lupus nephritis and nonrenal lupus. This article provides a discussion of several novel biologic agents at different stages of development for the treatment of SLE, as well as an analysis of newer data on agents that have been used in the treatment of SLE for many years.
"The antimalarial drug HCQ functions by increasing the pH of endosomal vesicles. This disrupts antigen processing and inhibiting toll-like receptor (TLR) 3, 7, 8, and 9 activity [29-31]; furthermore, HCQ can inhibit macrophage production of interleukin-1 and interleukin-6 . Since TLR7/9 have been implicated in inciting IFN-I production due to recognition of self RNA/DNA, the blockade of these TLRs could be attenuating IFN-I production and antigen processing for presentation of T cells by antigen-presenting cells such as dendritic cells. "
[Show abstract][Hide abstract] ABSTRACT: Our recent data showed that signal transducers and activators of transcription 1 (STAT1), adenosine deaminase acting on RNA (ADAR), C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine 10 (CXCL10) were significantly elevated in a systemic lupus erythematosus (SLE) cohort compared to healthy donors. High and low STAT1 subsets were identified in SLE patient visits. The present study analyzed the correlation of common treatments used in SLE with the levels of these biomarkers.
Peripheral blood leukocytes were collected from 65 healthy donors and 103 SLE patients, of whom 60 had samples from 2 or more visits. Total RNA was isolated and analyzed for the expression of mRNA and microRNA using Taqman real time polymerase chain reaction (PCR) assays. Relative expression of interferon signature genes, CCL2, and CXCL10 were determined by the DeltaDeltaCT method. Results were correlated with therapy using prednisone, mycophenolate mofetil, and hydroxychloroquine and analyzed by Wilcoxon/Kruskal-Wallis test and Fisher's exact test.
CCL2 and CXCL10 were significantly higher in untreated patients compared to treated patients, however, in high STAT1 patient visits there is no significant difference between treated and untreated patients' visits. When comparing linear regression fits of interferon (IFN) score with CCL2 and CXCL10, untreated patients and high STAT1 patients displayed significantly higher slopes compared to treated patients. There was no significant difference between the slopes of high STAT1 and untreated patients indicating that CCL2 and CXCL10 were correlated with type-I IFN in high STAT1 patients similar to that in untreated patients. CCL2 and CXCL10 levels in high STAT1 subset remained high in treated patient visits compared to those of the low STAT1 subset.
Among the biomarkers analyzed, only CCL2 and CXCL10 showed significantly reduced levels in treated compared to untreated SLE patients. STAT1, CCL2, and CXCL10 are potentially useful indicators of therapeutic action in SLE patients. Further work is needed to determine whether high STAT1 levels convey resistance to therapies commonly used to treat SLE and whether STAT1 inhibitors may have therapeutic implication for these patients.
"At present, therapy for SLE involves non-specific immunomodulatory agents that, while frequently effective, have many side effects, including serious infection from immunosuppression , . In view of the important role of anti-DNA in disease pathogenesis, investigators have explored more selective approaches to block the production of these antibodies or reduce their consequences –. "
[Show abstract][Hide abstract] ABSTRACT: Antibodies to DNA (anti-DNA) are the serological hallmark of systemic lupus erythematosus (SLE) and can mediate disease pathogenesis by the formation of immune complexes. Since blocking immune complex formation can attenuate disease manifestations, the effects of nucleic acid binding polymers (NABPs) on anti-DNA binding in vitro were investigated. The compounds tested included polyamidoamine dendrimer, 1,4-diaminobutane core, generation 3.0 (PAMAM-G3), hexadimethrine bromide, and a β-cylodextrin-containing polycation. As shown with plasma from patients with SLE, NABPs can inhibit anti-DNA antibody binding in ELISA assays. The inhibition was specific since the NABPs did not affect binding to tetanus toxoid or the Sm protein, another lupus autoantigen. Furthermore, the polymers could displace antibody from preformed complexes. Together, these results indicate that NABPs can inhibit the formation of immune complexes and may represent a new approach to treatment.
PLoS ONE 07/2012; 7(7):e40862. DOI:10.1371/journal.pone.0040862 · 3.23 Impact Factor
"The clinical presentation of SLE is influenced by a variety of factors including ethnicity, gender, age, socioeconomic factors, and age of onset . The typical course of the disease is illustrated by periods of disease flares alternating with waning disease activity, and the typical treatment of SLE consists of immunosuppressive medication, which clinically improves the condition of the patients . The etiology of SLE is believed to be multifactorial with genetic and environmental factors, both contributing to the development of this very complex disease. "
[Show abstract][Hide abstract] ABSTRACT: The etiology of SLE is not fully established. SLE is a disease with periods of waning disease activity and intermittent flares. This fits well in theory to a latent virus infection, which occasionally switches to lytic cycle, and EBV infection has for long been suspected to be involved. This paper reviews EBV immunobiology and how this is related to SLE pathogenesis by illustrating uncontrolled reactivation of EBV as a disease mechanism for SLE. Studies on EBV in SLE patients show enlarged viral load, abnormal expression of viral lytic genes, impaired EBV-specific T-cell response, and increased levels of EBV-directed antibodies. These results suggest a role for reactivation of EBV infection in SLE. The increased level of EBV antibodies especially comprises an elevated titre of IgA antibodies, and the total number of EBV-reacting antibody isotypes is also enlarged. As EBV is known to be controlled by cell-mediated immunity, the reduced EBV-specific T-cell response in SLE patients may result in defective control of EBV causing frequent reactivation and expression of lytic cycle antigens. This gives rise to enhanced apoptosis and amplified cellular waste load resulting in activation of an immune response and development of EBV-directed antibodies and autoantibodies to cellular antigens.
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